A concurrent engineering approach to develop BioMEMS employed in a deep brain stimulator integrated with a drug delivery system

This paper presents an Integrated Product Development (IPD) based model to specifically develop bio-medical micro-electro-mechanical-systems (BioMEMS). The concurrent engineering model is based on the IPD model phases, which are presented and formulated by the Integration DEFinition (IDEF) model- ling language. To evaluate the IPD model, a case study concerning the development of a BioMEMS device for a deep brain stimulation (DBS) system was investigated. By following the relevant mechanisms and controls in the model, a design concept of a wireless head-mounted DBS implant integrated with a drug delivery system (DDS) was conceived. The contribution of this paper is the IDEF model, which provides a road map to the product development team members in order to take a concurrent engineering approach to develop Bio-MEMS. The qualitative feedback received from the identified stakeholders, together with the quality of the case study employed, namely, an integrated DBS and DDS solution, indicate a degree of evidence that the model provides a sound basis in this direction.peer-reviewe

Design for micro milling guidelines

Miniaturisation of parts is emerging as an important approach to satisfy modern industrial and customer needs. Micro milling is one of the basic micromachining technologies used toproduce miniaturised components. It differs from conventional machining in that the handling and machining of very small features generates various problems. As a consequence, designers need to consider such problems during design to make micromilling more feasible. More emphasis thus needs to be placed on deriving design know-how from the other product life-phases. This paper reports the work undertaken by the Department of Manufacturing within the University of Malta to generate a set of Design for Micromilling (DFμM) guidelines that can contribute to the development to intelligent CAD for this domain.peer-reviewe

Bulk Metallic Glass based Tool-Making Process Chain for Micro- and Nano- Replication

Existing and emerging micro-engineered products tend to integrate a multitude of functionalities into single enclosures/packages. Such functions generally require different length scale features. In practice, devices having complex topographies, which incorporate different length scale features cannot be produced by employing a single fabrication technology but by innovatively, integrating several different complementary manufacturing techniques in the form of a process chain. In order to design novel process chains that enable such function and length scale integration into miniaturised devices, it is required to utilise materials that are compatible with the various component manufacturing processes in such chains. At the same time, these materials should be able to satisfy the functional requirements of the produced devices. One family of materials, which can potentially fulfil these criteria, is bulk metallic glasses (BMGs). In particular, the absence of grain boundaries in BMGs makes them mechanically and chemically homogeneous for processing at all length scales down to a few nanometres. In this context, this research presents an experimental study to validate a novel process chain. It utilizes three complementary technologies for producing a Zr-based BMG replication master for a microfluidic device that incorporates micro and nano scale features. Then, to validate the viability of the fabricated BMG masters, they are utilized for serial replication of the microfluidic device by employing micro-injection moulding

Country, Sex, EDSS Change and Therapy Choice Independently Predict Treatment Discontinuation in Multiple Sclerosis and Clinically Isolated Syndrome

We conducted a prospective study, MSBASIS, to assess factors leading to first treatment discontinuation in patients with a clinically isolated syndrome (CIS) and early relapsing-remitting multiple sclerosis (RRMS). The MSBASIS Study, conducted by MSBase Study Group members, enrols patients seen from CIS onset, reporting baseline demographics, cerebral magnetic resonance imaging (MRI) features and Expanded Disability Status Scale (EDSS) scores. Follow-up visits report relapses, EDSS scores, and the start and end dates of MS-specific therapies. We performed a multivariable survival analysis to determine factors within this dataset that predict first treatment discontinuation. A total of 2314 CIS patients from 44 centres were followed for a median of 2.7 years, during which time 1247 commenced immunomodulatory drug (IMD) treatment. Ninety percent initiated IMD after a diagnosis of MS was confirmed, and 10% while still in CIS status. Over 40% of these patients stopped their first IMD during the observation period. Females were more likely to cease medication than males (HR 1.36, p = 0.003). Patients treated in Australia were twice as likely to cease their first IMD than patients treated in Spain (HR 1.98, p = 0.001). Increasing EDSS was associated with higher rate of IMD cessation (HR 1.21 per EDSS unit, p<0.001), and intramuscular interferon-β-1a (HR 1.38, p = 0.028) and subcutaneous interferon-β-1a (HR 1.45, p = 0.012) had higher rates of discontinuation than glatiramer acetate, although this varied widely in different countries. Onset cerebral MRI features, age, time to treatment initiation or relapse on treatment were not associated with IMD cessation. In this multivariable survival analysis, female sex, country of residence, EDSS change and IMD choice independently predicted time to first IMD cessation

Aldo Keto Reductase 1B7 and Prostaglandin F2α Are Regulators of Adrenal Endocrine Functions

Prostaglandin F2α (PGF2α), represses ovarian steroidogenesis and initiates parturition in mammals but its impact on adrenal gland is unknown. Prostaglandins biosynthesis depends on the sequential action of upstream cyclooxygenases (COX) and terminal synthases but no PGF2α synthases (PGFS) were functionally identified in mammalian cells. In vitro, the most efficient mammalian PGFS belong to aldo-keto reductase 1B (AKR1B) family. The adrenal gland is a major site of AKR1B expression in both human (AKR1B1) and mouse (AKR1B3, AKR1B7). Thus, we examined the PGF2α biosynthetic pathway and its functional impact on both cortical and medullary zones. Both compartments produced PGF2α but expressed different biosynthetic isozymes. In chromaffin cells, PGF2α secretion appeared constitutive and correlated to continuous expression of COX1 and AKR1B3. In steroidogenic cells, PGF2α secretion was stimulated by adrenocorticotropic hormone (ACTH) and correlated to ACTH-responsiveness of both COX2 and AKR1B7/B1. The pivotal role of AKR1B7 in ACTH-induced PGF2α release and functional coupling with COX2 was demonstrated using over- and down-expression in cell lines. PGF2α receptor was only detected in chromaffin cells, making medulla the primary target of PGF2α action. By comparing PGF2α-responsiveness of isolated cells and whole adrenal cultures, we demonstrated that PGF2α repressed glucocorticoid secretion by an indirect mechanism involving a decrease in catecholamine release which in turn decreased adrenal steroidogenesis. PGF2α may be regarded as a negative autocrine/paracrine regulator within a novel intra-adrenal feedback loop. The coordinated cell-specific regulation of COX2 and AKR1B7 ensures the generation of this stress-induced corticostatic signal

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Technology maturity assessment of micro and nano manufacturing processes and process chains

This article presents a systematic approach for assessing the maturity of manufacturing technologies. A methodology is proposed that is based on modelling the capability of the individual processes and technology interfaces between them. It is inspired by a capability maturity model which has been applied successfully in the field of software engineering. The methodology was developed to assess the maturity levels of individual processes and the combined maturity of pairs or chains of processes. To demonstrate its validity, it was applied for assessing the maturity of technologies in the micro and nano manufacturing domain. The results demonstrated its applicability as a tool for evaluating the maturity of micro and nano manufacturing pairs and their constituent processes. Also, it was shown that the methodology can be employed for identifying process pairs, suitable for integration in process chains, together with their potential weaknesses

An industry 4.0 training framework addressing ‘COVID-19 type’ disruptions on manufacturing

Although digitization in the manufacturing industry has been going on for some years, the recent COVID-19 pandemic helped reveal a number of bottlenecks and challenges that still need to be overcome. Joint ongoing research by a number of European Universities aimed at developing a systematic training framework on Industry 4.0 happened to be performed in the midst of the pandemic. COVID-19 meant that suddenly, internal and external workers of different educational backgrounds and in different roles had to rapidly adapt to new working procedures and environments whilst learning to use new technologies. This disruption helped this research group to generate specifications of a Higher Education Industry 4.0 Training Framework (HEI4.0) that is relevant to foster skills and competencies that make manufacturing more resilient to other possible scenarios requiring social distancing limitations. This paper outlines the details of the research performed and contributes the concept and value of establishing what is termed as the ‘flow-cognitive profile chart’ of a manufacturing organization to effectively help it in its transition towards digital manufacturing. Based on this concept, the paper passes on to prescribe a HEI4.0 Training Framework intended to guide manufacturing organizations in addressing ‘COVID-19 type’ manufacturing disruptions that can take place in other future unforeseen circumstances.peer-reviewe